Objective: The focus of this study was: 1) to characterize the expression and the localization of an endogenous protease, tissue plasminogen activator (tPA) in the substantia nigra (SN), 2) to explore its role in neuroinflammation and neurodegeneration in a human α-synuclein (hα-syn) mouse model of Parkinson’s Disease (PD), and 3) to evaluate, in this model, the therapeutic effect of the inhibition of the interaction between tPA and endothelial N-methyl-D-aspartate receptor (NMDAR) by Glunomab, a monoclonal antibody.

Background: The therapeutic potential of Glunomab to counteract NMDAR modulation by tPA has been demonstrated in multiple animal models of neurological diseases. tPA is known to regulate different brain functions in both health and diseases; however, its role in the pathophysiology and its involvement in PD is unclear. In this study, we explored the effect of the deletion of tPA and of Glunomab administration on neuroinflammation and neurodegeneration in a hα-syn mouse model of PD.

Method: WT, tPA^-/- and mice overexpressing proteolytically inactive tPA were unilaterally injected with AAV-empty or AAV-hα-syn in the SN. Mice were evaluated after 4 weeks for lateralized neglect using the corridor task, tPA expression, dopaminergic neurodegeneration, and immune cell markers by immunohistochemistry and RNAseq.

Results: We identified tPA⁺ GABAergic striatal neurons innervating SN dopaminergic neurons and increased tPA protein in the SN upon AAV-hα-syn injection. Both tPA deficiency or Glunomab administration protected dopaminergic neurons from α-syn-induced degeneration, reduced microglia activation and T-cell infiltration and led to recovery of lateralized sensory-motor integration in the corridor task. RNAseq analysis in WT and tPA^-/- mice after AAV-hα-syn injection showed that overexpression of hα-syn in WT mice significantly upregulated genes involved in the innate and adaptive immune responses whereas their expression was not increased in tPA^-/- mice.

Conclusion: Our data shows that tPA promotes neuroinflammation and dopaminergic neurodegeneration induced by overexpression of α-syn, and that Glunomab prevents neurodegeneration by inhibiting tPA-induced neuroinflammation, translated into improved locomotion in a hα-syn mouse model of PD. This previously unidentified pathway suggests that Glunomab represents a promising novel immunotherapy for the treatment of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glunomab-a-novel-therapeutics-for-the-treatment-of-parkinsons-disease/